Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

Abstract

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

“…However, this led to only a moderate increase of success rates in identifying of genetic causes of IEI. 37,38 Christiansen et al, 39 As expected, use of stringent criteria for patient selection resulted in higher rates of identification of causative mutations. For example, pathogenic germ-line variants were identified in 25% patients with JMF signs for PID (Table 1).…”

The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID)

“…TTC37 gene is participated to cytosolic exosome’s large protein complex, and takes a part of inner cell abnormal mRNA degradation which has important role for cell growth. Genetic alterations in this gene were reported for specific antibody deficiency and defects in humoral memory 45 , 46 .…”

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults

“…Mutations detected in CVID patients include genes associated with impaired B-cell development (e.g., IKZF1 , BAFFR , TWEAK , CD27 , STAT1 GOF, NFKB2 , IRF2BP2 ), impaired CSR/SHM (e.g., BACH2 , IL21 , IL21R ), excessive lymphoproliferation (e.g., CTLA4 , LRBA , PIK3CD , STAT3 GOF), and impaired B-cell activation and tolerance (e.g., NFKB1 , TACI , CD19 , CD21 , ICOS , BLK , PLCG2 , CD81 , CD20 ) [ 88 , 135 , 138 , 139 ]. It is important to note that many of the genes mentioned above are also involved in SIgAD pathogenesis.…”